Endothelial IGFBP6 suppresses vascular inflammation and atherosclerosis.
Summary
IGFBP6 acts as an endothelial homeostatic mediator that dampens inflammatory signaling and monocyte adhesion via an MVP–JNK/NF-κB pathway. Human, cellular, and mouse data converge to show that loss of IGFBP6 predisposes to atherosclerosis, whereas endothelial overexpression is protective, nominating IGFBP6 as a potential therapeutic target.
Key Findings
- IGFBP6 is reduced in human atherosclerotic arteries and patient serum.
- Endothelial IGFBP6 knockdown increases inflammatory gene expression and monocyte adhesion; overexpression reverses TNF and disturbed-flow effects.
- Anti-inflammatory effects operate via MVP–JNK/NF-κB signaling.
- IGFBP6-deficient mice develop aggravated diet- and disturbed-flow-induced atherosclerosis, while endothelial IGFBP6 overexpression is protective.
Clinical Implications
IGFBP6 augmentation or mimetics could represent a novel anti-inflammatory strategy for atherosclerosis beyond lipid-lowering, and circulating IGFBP6 might serve as a biomarker of vascular inflammatory risk.
Why It Matters
This work uncovers a previously unrecognized endothelial brake on vascular inflammation with clear mechanistic elucidation and in vivo validation, directly linking basic biology to atherosclerosis pathogenesis.
Limitations
- Preclinical study without interventional human trials; translational dosing and delivery of IGFBP6 remain unknown.
- Potential off-target or context-specific effects of IGFBP6 modulation not fully explored.
Future Directions
Develop IGFBP6-based therapeutics (protein, gene therapy, or small-molecule upregulators), validate circulating IGFBP6 as a biomarker, and assess efficacy/safety in large animal models and early-phase trials.
Study Information
- Study Type
- Basic/Mechanistic research
- Research Domain
- Pathophysiology
- Evidence Level
- V - Preclinical mechanistic evidence integrating human tissues, in vitro, and in vivo models
- Study Design
- OTHER